Medical Education - Research Publications
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ItemAutoantibodies against voltage-gated potassium channel and glutamic acid decarboxylase in psychosis: A systematic review, meta-analysis, and case series.(Wiley, 2017-10)Antibodies to the voltage-gated potassium channel (VGKC) complex and glutamic acid decarboxylase (GAD) have been reported in some cases of psychosis. We conducted the first systematic review and meta-analysis to investigate their prevalence in people with psychosis and report a case series of VGKC-complex antibodies in refractory psychosis. Only five studies presenting prevalence rates of VGKC seropositivity in psychosis were identified, in addition to our case series, with an overall prevalence of 1.5% (25/1720) compared to 0.7% in healthy controls (12/1753). Meta-analysis established that the pooled prevalence of GAD65 autoantibodies was 5.8% (95% confidence interval [CI]: 2.0-15.6%; I2 = 91%; nine studies) in psychotic disorders, with a prevalence of 4.6% (95%CI: 1.2-15.9%; nine studies; I2 = 89%) and 6.2% (95%CI: 1.2-27.0%; two studies; I2 = 69%) in schizophrenia and bipolar disorder, respectively. People with psychosis were more likely to have GAD65 antibodies than controls (odds ratio [OR], 2.24; 95%CI: 1.28-3.92%; P = 0.005; eight studies; I2 = 0%). Among 21 participants with treatment-resistant psychosis, none had VGKC antibodies. The prevalence of VGKC antibodies is low in psychosis. Our preliminary meta-analysis suggests that GAD autoantibodies are more common in people with psychosis than in controls, although few studies accounted for the possibility of co-existing type 1 diabetes mellitus and the clinical significance of reported GAD titers remains unclear. The paucity of studies reporting thresholds for defining GAD abnormality and rates of comorbid type 1 diabetes mellitus precludes interpretations regarding the influence of GAD antibodies on the development of psychotic disorders and may have led to an overestimate of the prevalence of GAD. Our case series fails to support the hypothesis that VGKC antibodies are linked to treatment resistance in psychosis, but the literature to date is remarkably sparse.
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ItemThe impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder1.(Wiley, 2017-04)Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737.
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ItemAre deficits in cognition associated with psychotic-like experiences after cannabis?(Wiley, 2016-11)UNLABELLED: Not all individuals who smoke cannabis report psychotic-like experiences. Given that risk factors for psychotic disorders are multifaceted, precipitating factors to psychotic-like experiences after cannabis are likely to be equally complex. Reduced neurocognitive performance is associated with both psychosis risk and cannabis use. Therefore, it is possible cognitive performance may differentiate those who report psychotic-like experiences after cannabis from those who do not. We determined whether those reporting psychotic/dysphoric experiences after cannabis had reduced neurocognitive performance compared to those reporting primarily euphoric experiences. METHODS: Participants were recruited on the basis of responses to the cannabis high captured by the Psychosis-Dysphoric and Euphoric experiences subscales from the Cannabis Experiences Questionnaire (CEQ). RESULTS: Compared to participants reporting primarily euphoric cannabis experiences (n = 36; 44% male; mean age (SD) = 28 (9) years), those who reported psychotic/dysphoric experiences (n = 40; 45% male; mean age (SD) = 26 (5) years) demonstrated significantly faster responses to a trial and error learning task. In the presence of distracters, those with psychotic/dysphoric experiences after cannabis made more errors on a Continuous Performance Task. CONCLUSIONS: Those who report psychotic/dysphoric experiences after cannabis have subtle inefficiencies in their cognitive processes. The multiple factors which predict vulnerability to psychotic-like experiences after cannabis require further investigation.
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ItemSubstance use and at-risk mental state for psychosis in 2102 prisoners: the case for early detection and early intervention in prison(WILEY, 2018-06)AIM: Prisoners exhibit high rates of substance use and mental health problems. In the present study, we sought to gain a detailed understanding of substance use amongst young prisoners to inform early detection and early intervention strategies in a prison setting. METHODS: This is a cross-sectional study of 2102 prisoners who were screened by the London Early Detection and Prevention in Prison Team (LEAP). Data on the use of substances were collected including age of first use, recent use, duration of use and poly-drug use. The Prodromal Questionnaire - Brief Version was used to screen for the at-risk mental state. RESULTS: We found high rates of lifetime and recent use and low age of first use of a number of substances. We also found strong associations between substance use and screening positive for an at-risk mental state. Logistic regression analysis confirmed that use of any drug in the last year, poly-drug and early use, as well as heavy alcohol use, were related to an increased risk of screening positive. CONCLUSIONS: Substance use in the prison population is not only widespread and heavy but is also strongly linked with a higher risk of developing mental health problems. The need for early detection and early intervention in prison is discussed.
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ItemOccupation and first episode psychosis in Northern Italy: better outcomes for migrants.(Wiley, 2017-12)AIMS: Many studies show that migrants have a higher incidence of psychosis compared to natives, but the influence of migration on psychosis outcomes is little investigated. We aimed to evaluate the occupational outcomes of a first episode psychosis (FEP) sample in Bologna (Northern Italy). METHODS: An incidence cohort of FEP patients presenting at the Bologna West Community Mental Health Centers between 2002 and 2009 was assessed at the baseline and at 12th month follow-up. Return to school or work was used as occupational outcome. RESULTS: Most of the patients (82.8%) were still in contact at 12 months. Migrants showed significantly higher rate of return to work compared to natives (adjusted OR 4.45, 95% CI 1.55-12.76). CONCLUSIONS: First generation migrants had better occupational outcomes. Further cross-cultural studies are needed to further explain these findings.
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ItemCortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium(ELSEVIER SCIENCE INC, 2018-11-01)BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.
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ItemThe effect of psychosis associated CACNA1C, and its epistasis with ZNF804A, on brain function.(Wiley, 2019-04)CACNA1C-rs1006737 and ZNF804A-rs1344706 polymorphisms are among the most robustly associated with schizophrenia (SCZ) and bipolar disorder (BD), and recently with brain phenotypes. As these patients show abnormal verbal fluency (VF) and related brain activation, we asked whether the latter was affected by these polymorphisms (alone and in interaction)-to better understand how they might induce risk. We recently reported effects on functional VF-related (for ZNF804A-rs1344706) and structural (for both) connectivity. We genotyped and fMRI-scanned 54 SCZ, 40 BD and 80 controls during VF. With SPM, we assessed the main effect of CACNA1C-rs1006737, and its interaction with ZNF804A-rs1344706, and their interaction with diagnosis, on regional brain activation and functional connectivity (psychophysiological interactions-PPI). Using public data, we reported effects of CACNA1C-rs1006737 and diagnosis on brain expression. The CACNA1C-rs1006737 risk allele was associated with increased activation, particularly in the bilateral prefronto-temporal cortex and thalamus; decreased PPI, especially in the left temporal cortex; and gene expression in white matter and the cerebellum. We also found unprecedented evidence for epistasis (interaction between genetic polymorphisms) in the caudate nucleus, thalamus, and cingulate and temporal cortical activation; and CACNA1C up-regulation in SCZ and BD parietal cortices. Some effects were dependent on BD/SCZ diagnosis. All imaging results were whole-brain, voxel-wise, and familywise-error corrected. Our results support evidence implicating CACNA1C and ZNF804A in BD and SCZ, adding novel imaging evidence in clinical populations, and of epistasis-which needs further replication. Further scrutiny of the inherent neurobiological mechanisms may disclose their potential as putative drug targets.
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ItemAge at first birth in women is genetically associated with increased risk of schizophrenia(NATURE PORTFOLIO, 2018-07-05)Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.
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ItemDoes environmental confounding mask pleiotropic effects of a multiple sclerosis susceptibility variant on vitamin D in psychosis?(Springer Science and Business Media LLC, 2015)BACKGROUND: This work addresses the existing and emerging evidence of overlap within the environmental and genetic profiles of multiple sclerosis (MS) and schizophrenia. AIMS: To investigate whether a genetic risk factor for MS (rs703842), whose variation is indicative of vitamin D status in the disorder, could also be a determinant of vitamin D status in chronic psychosis patients. METHODS: A cohort of 224 chronic psychosis cases was phenotyped and biologically profiled. The relationship between rs703842 and physiological vitamin D status in the blood plasma was assessed by logistic regression. Deficiency was defined as a blood plasma concentration below 10 ng/µl. Potential environmental confounders of the vitamin D status were considered as part of the analysis. RESULTS: We report suggestive evidence of an association with vitamin D status in established psychosis (ß standardized=0.51, P=0.04). The logistic model fit significantly benefited from controlling for body mass index, depression and ethnicity (χ (2)=91.7; 2 degrees of freedom (df); P=1.2×10(20)). CONCLUSIONS: The results suggest that, in addition to lifestyle changes that accompany the onset of illness, vitamin D dysregulation in psychosis has a genetic component that links into MS. Further, comprehensive studies are needed to evaluate this prospect.
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ItemInteraction between DRD2 and AKT1 genetic variations on risk of psychosis in cannabis users: a case-control study.(Springer Science and Business Media LLC, 2015)